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Logo of ajcnThe American Journal of Clinical NutritionSearchSubmit ManuscriptSubscribeAll ArticlesPublished Version
Am J Clin Nutr. Nov 2010; 92(5): 1204–1213.
Published online Sep 8, 2010. doi:  10.3945/ajcn.2010.29494
PMCID: PMC2954452

Relation of omega-3 fatty acid and dietary fish intake with brachial artery flow-mediated vasodilation in the Multi-Ethnic Study of Atherosclerosis1,2,3

Abstract

Background: The relation between dietary fish intake and brachial artery measures, including brachial artery flow-mediated dilation (FMD), has not been well established across sex and racial-ethnic groups.

Objective: We hypothesized that consumption of nonfried fish and plasma phospholipid measures of long-chain omega-3 (n–3) fatty acids would be positively associated with larger FMD in men and women across racial-ethnic groups.

Design: We investigated cross-sectional associations of brachial artery measures with fish intake (ascertained with a food-frequency questionnaire) and plasma phospholipid omega-3 concentrations in 3045 adults, aged 45–84 y, who were free of clinical cardiovascular disease.

Results: In overall multivariate-adjusted analyses, there were no significant associations between fish intake or any brachial artery measures. However, when stratified by sex, there was an association between the highest quartile of nonfried fish consumption and a 0.10-mm lower (1 SD) brachial artery diameter in men (P = 0.01) and a 0.27% smaller FMD in women (P = 0.02) compared with the lowest quartile of nonfried fish intake in each respective sex strata. When stratified by race-ethnicity and race-ethnicity by sex, additional heterogeneity was noted, but results were difficult to interpret because of small sample sizes. Plasma phospholipid omega-3 concentrations showed a similar directionality of association with brachial artery measures observed for nonfried fish consumption, although statistical significance was not achieved in fully adjusted models.

Conclusion: This study indicates that the association between nonfried fish intake and baseline brachial artery size varies by sex, with suggestive evidence of sex differences in the association between nonfried fish intake and FMD.

INTRODUCTION

Multiple epidemiologic, observational, and interventional studies have shown an inverse relation between fish consumption and cardiovascular events and death (16). Several mechanisms have been reported that may be responsible for these beneficial associations (710). One purported mechanism includes the effect of omega-3 (n−3) fatty acids on lipid bilayer composition and subsequent improvement in membrane fluidity, which may play an important role in endothelial function (1113).

Flow-mediated dilation (FMD) is a noninvasive surrogate for endothelial function, which is, in part, dependent on endothelial production and the release of nitric oxide (1416). Large, prospective cohort studies suggested that FMD may be a useful tool to evaluate early atherosclerotic disease, particularly in healthy individuals with low Framingham risk scores, and a larger FMD has been shown to be predictive of decreased incident cardiovascular events (fully adjusted hazard ratios ranged from 0.84 to 0.91) (1720). FMD has also been shown to be influenced by the intake of fish oils in randomized trials with durations as short as 2 wk (21, 22). However, there are few studies that examined the effects of dietary fish consumption on FMD, and the relation between fish intake and FMD in different racial-ethnic groups are lacking.

The main objective of the current study was to examine the relations of endothelial dysfunction, as measured by FMD, with fish intake and concentrations of plasma phospholipid omega-3 fatty acid [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] by using data from the Multi-Ethnic Study of Atherosclerosis (MESA). We hypothesized that consumption of nonfried fish foods as well as plasma phospholipid EPA and DHA concentrations would be positively associated with larger FMD in men and women across racial-ethnic groups. In addition, we examined the relation of other brachial artery measures (baseline brachial diameter and maximal diameter) with fish intake and plasma phospholipid omega-3 fatty acid concentrations for exploratory purposes because others observed an association of increased cardiovascular events with larger baseline brachial artery diameters (17, 18).

METHODS

Study population and data collection

MESA is a prospective cohort study that began in July 2000 to investigate the prevalence, correlates and progression of subclinical cardiovascular disease (CVD) in individuals without known CVD at baseline. The main cohort included 6814 women and men aged 45–84 y old at baseline who were recruited from 6 US communities (Baltimore, MD; Chicago, IL.; Forsyth County, NC; Los Angeles County, CA; northern Manhattan, NY; and St Paul, MN). MESA cohort participants were 38% white (n = 2624), 28% black (n = 1895), 22% Hispanic (n = 1492), and 12% Chinese (n = 803). Details of the MESA study design were documented previously (23). A variety of noninvasive measures of subclinical disease, including brachial FMD, were obtained during the first examination of the MESA cohort (July 2000 to August 2002). In the current study, we excluded subjects who had missing data on both fish intake (n = 364) and brachial FMD (n = 3589) and subjects with missing covariates that were used in the study (n = 92). The total sample size after these exclusions was 3045. This study was approved by the Institutional Review Boards of each study site, and written informed consent to participate in the study was obtained from all participants.

Dietary assessment

A detailed description of the MESA food-frequency questionnaire (FFQ) was described previously (24). At baseline, participants recorded the serving size (small, medium, or large) and frequency (times per day, week, or month) that they consumed each FFQ item. Responses were converted to servings per day by multiplying consumption frequency by reported serving size, with weights of 0.5, 1.0, and 1.5 applied to small, medium, and large serving sizes, respectively (24).

The MESA FFQ was modified from the FFQ used in the Insulin Resistance Atherosclerosis Study to include unique Chinese foods and to collect supplemental information (23, 25). The validity of the FFQ was assessed by comparison with eight 24-h dietary recalls in non-Hispanic white, black, and Hispanic persons in the Insulin Resistance Atherosclerosis Study (25). Ten FFQ items included information about fish and shellfish consumption, which were then categorized by types as follows: nonfried fish (2 items; 1) tuna, salmon, sardines, sashimi, or sushi and 2) other broiled, steamed, baked, or raw fish, such as trout, sole, halibut, poke, and grouper); shellfish (1 item; nonfried shrimp, lobster, crab, oysters, and mussels); fish-containing mixed dishes (6 items; fish in enchiladas, burritos, quesadilla, pasta, stew, gumbo, paella, and salad); and fried fish (1 item; any fried fish or fish sandwich, fried shrimp, and calamari). A recent validation study in dietary macronutrient intake and plasma lipids showed the criterion performance of the MESA FFQ (26), and associations between fish intake and plasma fatty acids were previously reported (27). In addition, we confirmed a positive, statistically significant association between nonfried fish intake and plasma phospholipid EPA and DHA concentrations within our sample population (overall r = 0.29, P < 0.0001; data not shown). The strength of this relation was similar to that observed by others (28), and other types of fish did not show significant relations with fatty acids after adjustment for nonfried fish.

For statistical analyses, the frequency of fish consumption was further classified into 4 main categories for each fish type 1): rare or never, 2) 1–3 times/mo, 3) 1–2 times/wk, and 4) >2 times/wk. Quartiles ranks were created on the basis of the sample range. This strategy was adopted on the basis of previous data that showed a threshold effect of nonfried fish intake, with consumption of nonfried fish once weekly resulting in remarkably lower incidence of sudden cardiac death compared with little or no nonfried fish intake, as well as on the basis of data that suggested a plateau effect with a nonfried fish intake of twice weekly (27, 28). Additional analyses including comparisons of <1 serving compared with ≥1 serving of nonfried fish/wk on brachial measures were also examined within this cohort, and similar patterns were observed (data not shown).

Plasma phospholipid extraction

Fasting blood samples were collected, and plasma phospholipid fatty acid analyses were performed at the Collaborative Studies Clinical Laboratory at Fairview-University Medical Center (Minneapolis, MN) as previously described (n = 1642) (23, 29). In brief, plasma lipids were extracted with chloroform and methanol, and thin layer chromatography was used to separate the lipid fractions and isolate phospholipids. Fatty acids were assessed by using gas chromatography with a flame ionization detector, and the concentration of each fatty acid was expressed as a percentage of the total fatty acids. Because EPA and DHA are found together in fatty fish, and therefore, plasma phospholipid values are highly correlated (30), plasma phospholipid concentrations of EPA and DHA were summed for each subject. For statistical analyses, quartile ranks were created on the basis of the sample range of these sums.

Brachial FMD measurement

Brachial FMD was measured in the MESA cohort during the first examination. Participants were excluded if they had uncontrolled hypertension (158 MESA participants were excluded), blood pressures in the left and right arms that differed by >15 mm Hg, a history of Raynaud's phenomenon (55 MESA participants were excluded), a congenital abnormality of the arm or hand (12 MESA participants were excluded), or a radical mastectomy on either side (100 MESA participants were excluded). Participants were examined in the supine position after 15 min rest and after a fast of ≥6 h. A standard blood pressure cuff was positioned around the right arm, 2 inches below the antecubital fossa, and the artery was imaged 5–9 cm above the antecubital fossa. A linear-array multifrequency transducer that operated at 9 MHz (GE Logiq 700 Device; Fairfield, CT) was used to acquire images of the right brachial artery. After obtaining baseline images, the cuff was inflated to 50 mm Hg above the participant's systolic blood pressure for 5 min. Digitized images of the right brachial artery were captured continuously for 30 s before cuff inflation and for 2 min beginning immediately before cuff deflation to document the vasodilator response. A detailed description of the scanning and reading protocol can be found at the MESA website (http://www.mesa-nhlbi.org).

An analysis of the brachial artery videotapes was performed in a nested case-cohort of MESA participants that involved a random sample of MESA participants (subcohort; n = 2,844) and all participants who had an adjudicated cardiovascular event by 10 October 2005 (cases; n = 182). The videotapes were analyzed at the Wake Forest University Cardiology Image Processing Laboratory by using a previously validated semiautomated system (11). The semiautomated readings (media-adventitial interfaces to media-adventitial interfaces) of these digitized images generated the baseline and maximum diameters of the brachial artery from which the percentage FMD was computed as follows:

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Correlations for repeated measures of baseline diameter, maximum diameter, and percentage FMD were obtained with an original read and a quality-control read scanned on 2 separate days in 40 MESA participants (32 men; 18 white, 2 Chinese, 10 African American, and 10 Hispanic participants) were 0.99, 0.99, and 0.81, respectively.

Statistical analyses

Means and SDs or proportions were calculated for selected variables according to the 4 categories of nonfried fish consumption (Table 1). For the primary analysis, the following regression models were used to examine the association between fish consumption (separately by fish type) and brachial artery measures: baseline diameter, maximum diameter after the flow stimulus, and absolute and percentage changes in brachial diameter (percentage FMD). Minimally adjusted (age) and fully adjusted models were used to examine these relations. On the basis of previously published research and univariate tests, we considered a number of potential confounders for inclusion in the fully adjusted models, including BMI, systolic and diastolic blood pressure, diabetes diagnosis (by using the 2003 American Diabetes Association fasting criteria algorithm) (31), hypertension medication, serum triglyceride concentration, ratio of serum total:HDL cholesterol, lipid-lowering medication, exercise, tobacco pack-years, current and former smoking status, alcohol intake, income, education, menopausal status, current hormone replacement therapy, total caloric intake, percentage saturated fat intake, α-linolenic acid intake, linoleic acid intake, vitamin/mineral supplement use (including vitamins C and E and folate), and polyphenolic-rich food intake (highest quintile compared with others). However, fish intake may influence brachial artery measures via modification of plasma lipid concentrations and blood pressure (ie, inclusion of these variables might represent overadjustment). The inclusion or exclusion of these variables as covariates did not significantly alter the relation between fish intake and brachial FMD. Thus, these covariates were not retained in the final multivariable adjusted model, which included age, sex, race-ethnicity, BMI, current smoking status, educational level, income level, and (in women only) current hormone replacement therapy. Because sex differences in fatty acid metabolism and tissue levels have been described (32, 33), and racial-ethnic differences have been observed in FMD (34), we also chose to stratify analyses by sex and race-ethnicity. When there appeared to be significant differences in fish and brachial artery measures by sex as well as race-ethnicity, formal tests for interaction were performed by using the product of fish × sex and fish × race-ethnicity in separate models. In additional analyses, the association between plasma phospholipid EPA + DHA concentrations and brachial dimensions were examined by using similar age-adjusted and fully adjusted linear models. Stratification by sex and race-ethnicity were also performed for plasma EPA + DHA concentrations for the reasons previously cited; when there appeared to be significant differences in plasma phospholipid EPA + DHA concentrations and brachial artery measures by sex and/or race-ethnicity, formal tests for interactions were performed (ie, the product of EPA + DHA × sex and of EPA + DHA × race-ethnicity were included in separate models). All P values were 2-sided, and a P value ≤0.05 was considered significant. We used JMP version 8.0 software (SAS Institute Inc, Cary, NC) for analyses.

TABLE 1
Sample characteristics classified by frequency of nonfried fish intake1

RESULTS

Participant characteristics

Characteristics of participants according to intakes of nonfried fish are presented in Table 1. Greater nonfried fish consumption was associated with older age, white and Chinese race-ethnicity, lower BMI, higher education, higher income, less tobacco use, lower systolic blood pressure, lower blood lipid concentrations, and a lower prevalence of diabetes. Greater nonfried fish consumption was also associated with lower saturated fat intake and a higher consumption of fruit and vegetables, although greater intake was also associated with lower physical activity levels.

The numbers of subjects in each of the nonfried fish categories were roughly similar overall and after stratification for sex. The median intake of the sex- and race-ethnicity–combined sample was ≈3 servings/mo, which corresponded to a median plasma phospholipid EPA + DHA percentage of 4.87 ± 2.33%. Of participants, Hispanics consumed nonfried fish the least frequently, with a median intake of 1 time/mo, followed by blacks (median intake: 2–3 times/mo). Whites and Chinese consumed nonfried fish most frequently (median intake: 1 time/wk and 2 times/wk, respectively). When further stratified by sex and race-ethnicity, values were similar. Intakes of other fish groups also showed similar patterns (data not shown).

Fish consumption and brachial artery measures

After adjustment for age, the highest quartiles of nonfried fish intake were significantly associated with a smaller baseline brachial artery diameter compared with that of the lowest quartile of intake (P < 0.0001); however, after adjustment for other covariates, this association was no longer significant (Table 2). There were no other significant associations between nonfried fish intake and brachial artery measures in either the age-adjusted or fully adjusted overall models.

TABLE 2
Brachial artery measures and nonfried fish intake by sex1

When analyses were stratified by sex, a significant inverse relation between nonfried fish intake and baseline diameters was observed in men (Table 2). In contrast, in women, greater nonfried fish intake was associated with larger baseline diameters (P = NS) and a smaller percentage FMD (P = 0.02; Table 2). Simple inspection of the data comparing men with women suggest that the frequency of nonfried fish intake presented as opposing U-shaped patterns for baseline artery diameter and FMD (Figure 1). Tests of interactions between sex and nonfried fish intake for baseline diameter and percentage FMD were performed, and a significant interaction was noted between sex and nonfried fish intake for baseline diameter (P = 0.0001 for baseline diameter; P = 0.09 for percentage FMD). No other significant associations of any brachial artery measure with consumption of other fish types were observed.

FIGURE 1.
Least-squares means (±SDs) of brachial artery measures and concentrations of plasma phospholipid eicosapentaenoic acid and docosahexaenoic acid (EPA+DHA) compared with nonfried fish intake by sex. Results shown were adjusted for age, race-ethnicity, ...

Because other researchers observed significant racial-ethnic differences in FMD (34), data were additionally stratified by race-ethnicity, and a significant inverse association was observed between nonfried fish intake and baseline artery diameters in Hispanics (Table 3). Tests of interaction by race-ethnicity were examined and were not significant. Data were further stratified by race-ethnicity and sex, and in these stratified analyses, an inverse association between nonfried fish intake and baseline artery diameters were significant in Hispanic men (P = 0.01; data not shown), and an inverse relation between nonfried fish intake and raw FMD (mm change) was significant in Chinese women only (P = 0.03; data not shown). However, the numbers of participants within each of these subgroups were small (eg, n = 367 for Hispanic men, and n = 302 for Chinese women).

TABLE 3
Brachial artery measures and nonfried fish intake by racial-ethnic group1

Plasma phospholipid EPA + DHA and FMD

Similar to observations of other MESA investigators (who used a different sample size and selection criteria) (27), plasma phospholipid EPA + DHA concentrations were significantly positively correlated with nonfried fish intake across all races and in men and women within our subsample of participants (r = 0.28 for men and women, P < 0.0001; data not shown). Consistent with dietary nonfried fish consumption, there was an inverse relation noted between baseline artery diameters and plasma phospholipid EPA + DHA concentrations in men, although results were only significant in the age-adjusted model (P = 0.003 in the age-adjusted model; data not shown; P = 0.16 in the fully adjusted model; Figure 1). In women, a pattern that paralleled the relation with dietary nonfried fish intake and FMD was also observed, but this was not significant (Figure 1). When data were stratified by race-ethnicity, significant inverse associations were observed between plasma phospholipid EPA + DHA concentrations and baseline diameters in Chinese and Hispanics in age-adjusted models but not in fully adjusted models. In addition, a borderline significant association between plasma phospholipid EPA + DHA concentrations and FMD in blacks was observed in fully adjusted models (P = 0.04 for the millimeter change in FMD; P = 0.06 for percentage change in FMD; Table 4) but not in age-adjusted models. Tests for interactions of EPA + DHA × brachial artery measures were nonsignificant (P = 0.92). Stratification by sex in addition to race-ethnicity revealed no significant associations between plasma phospholipid EPA + DHA concentrations and brachial measures (data not shown).

TABLE 4
Brachial artery measures and plasma phospholipid eicosapentaenoic acid and docosahexaenoic acid (EPA + DHA) concentrations by racial-ethnic group1

DISCUSSION

In the current study, in which we examined the relation between fish consumption and noninvasive measures of endothelial function across racial-ethnic groups, the main finding was that increasing quartiles of nonfried fish intake resulted in disparate responses in baseline artery diameters and FMD in men compared with women. Visual inspection of the data suggested a nearly mirror-image relation among these brachial measures by sex, although statistical significance was only observed for baseline artery diameters in men and FMD in women (Table 2, Figure 1). The second finding of this study was that stratification by race-ethnicity revealed a significant inverse association between nonfried fish intake and baseline artery diameters in Hispanics (Table 3), and although some significant associations were detected between nonfried fish and brachial artery measures after further stratification by sex, sample sizes were quite small and results were difficult to interpret with confidence. Last, similar patterns were also observed between plasma phospholipid EPA + DHA concentrations and brachial artery measures when stratified by sex and race-ethnicity, although results were not significant in each case (Table 4; Figure 1).

The clinical implications of these findings are not yet certain. Other MESA investigators showed associations between nonfried fish consumption and lower concentrations of inflammatory biomarkers and markers of endothelial activation (27, 36). In addition, greater FMD and smaller baseline artery diameters were associated with decreased incident cardiovascular events within the MESA cohort (18), and an inverse relation between FMD and left ventricular mass has also been noted (35). Our subsample had a median plasma phospholipid EPA + DHA concentration that was comparable with that observed by others in subjects with similar intakes of nonfried fish and would be expected to reduce the incidence of sudden cardiac death substantially compared with the risk for individuals in the lowest quartile of nonfried fish intake (37). Thus, the inverse association between nonfried fish intake and FMD observed in women in the current study is unexpected. Additional analyses are warranted to determine whether the relation between nonfried fish intake (and plasma phospholipid concentrations) and other cardiovascular outcomes also vary by sex.

Several lines of evidence suggest there may be important sex differences in metabolic, physiologic, or clinical consequences of dietary fat consumption (3840). Unfortunately, there are few studies in women that examined the relation between omega-3 fatty acid or fish intake and clinical correlates of CVD and/or incident events, and even fewer studies have included women of different racial-ethnic groups. Although the Nurse's Health Study clearly showed a cardioprotective effect of nonfried fish consumption in a large population of white women (41), results from a recent 12-y prospective cohort of men and women of mixed racial-ethnic groups failed to demonstrate a significant protective effect of nonfried fish consumption in women (42). Of interest, an increased risk in incident cardiovascular events in those who consumed more salted and dried fish was observed within this cohort (42).

Some previous data suggested that omega-3 fatty acid metabolism differs between men and women. Population surveys from New Zealand, the United Kingdom, and Canada showed women had a greater tissue DHA content compared with that of men, regardless of dietary omega-3 intakes, and some population surveys showed variable tissue EPA and docosapentaenoic acid (DPA) contents as well (4346). Evidence from stable-isotope feeding studies also showed differences in omega-3 metabolism, with women demonstrating a higher capacity to metabolize α-linolenic acid to DHA than did men (32, 47). However, it was also postulated that women may have less ability to retroconvert DHA to EPA and DPA, and experimental studies showed that hormone replacement therapy inhibited such retroconversion (48). Clinical implications of these findings are unclear because both EPA and DHA had beneficial effects on cardiovascular risk factors. It is possible that EPA compared with DHA exhibited varying mechanisms of action on inflammation, lipid oxidation, nitric oxide, or other modulators of endothelial function (49).

To our knowledge, the current study is unique in that it examined fish consumption separately in men and women of 4 different racial-ethnic groups and also examined plasma phospholipid EPA + DHA concentrations. Although our results are not consistent with other research that showed a significant improvement in FMD after feeding fish oil supplements to subjects (21, 22), our study differed in that dietary whole fish was examined. Furthermore, this was not a feeding trial that examined a clinical outcome, but rather, this study was conducted in an ethnically diverse cohort who consumed their own native diet. Although the observed differences between men and women were unexpected, the inconsistency between men and women of similar racial-ethnic groups suggests that this disparity is unlikely to be fully explained by food-preparation methods alone (ie, Chinese men and women, whom we expected would have similar methods of fish preparation, differed in FMD results; this was also the case for Hispanic men compared with women). The similar results noted between brachial artery measures and plasma phospholipid EPA + DHA concentrations, which were correlated with nonfried fish intake, further support these findings.

The strengths of this study include the ethnically diverse population, the inclusion of men and women, the large overall sample size, and the availability of detailed dietary information as well as objective measures of endothelial function. The limitations of the study include the observational cross-sectional study design with its known inability to infer causation and the potential for temporal bias, as well as several limitations in the MESA diet questionnaire. Because the diet questionnaire was not designed to specifically assess fish and long-chain fatty acid intake, some potentially key details were lacking, such as separate data on amounts of oily fish consumed, the freshness of the fish, and the fish preparation and cooking methods. Furthermore, like any observational study, there remains the possibility of residual confounding for factors (such as health status) or differential recall related to food intakes that could have meaningful effects on the observed results. It is also possible that our findings are reflective of spurious associations that resulted from multiple testing. However, despite these potential shortcomings, previous data from MESA speak to the construct validity of the assessment of fish intake in this population (27, 36). Finally, we must also consider the possibility of measurement error within the multiple measures of brachial artery diameters, which could have diminished our ability to observe significant associations. Although the intraindividual variability of FMD is notable (50), the cross-sectional design of this large population study reduced the potential significance of such an inconsistency.

In conclusion, this study adds to the small but growing body of evidence that diet may have differential effects on cardiovascular outcomes in women compared with in men. Within this cohort of mixed racial-ethnic groups without known coronary artery disease, the associations of nonfried fish consumption with brachial artery measures varied by sex. Similar associations were observed between plasma phospholipid EPA + DHA concentrations and brachial artery measures. Additional analyses provided suggestive evidence of differences by race-ethnicity as well as race-ethnicity by sex. Future studies are warranted to clarify the extent to which sex may modify the relation between polyunsaturated fatty acids and cardiovascular outcomes.

Acknowledgments

We thank the other investigators, staff, and participants of the MESA for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.

The authors' responsibilities were as follows—JSA: conception and design, data collection, statistical analysis, interpretation of the data, drafting of the manuscript, critical revision of the manuscript for important intellectual content, and approval of the final manuscript for submission; JAN and MYT: interpretation of the data, critical revision of the manuscript for important intellectual content, and approval of the final manuscript for submission; DMH: conception and design, obtained funding, statistical advice, interpretation of the data, critical revision of the manuscript for important intellectual content, and approval of the final manuscript for submission; WCJ: interpretation of the data, statistical advice, critical revision of the manuscript for important intellectual content, and approval of the final manuscript for submission; and DS: conception and design, interpretation of the data, critical revision of the manuscript for important intellectual content, and approval of the final manuscript for submission. None of the authors had a conflict of interest.

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